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Ref Type | Journal Article | ||||||||||||
PMID | (23908597) | ||||||||||||
Authors | Byron SA, Chen H, Wortmann A, Loch D, Gartside MG, Dehkhoda F, Blais SP, Neubert TA, Mohammadi M, Pollock PM | ||||||||||||
Title | The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib, and ponatinib ATP-competitive inhibitors. | ||||||||||||
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Abstract Text | We sought to identify fibroblast growth factor receptor 2 (FGFR2) kinase domain mutations that confer resistance to the pan-FGFR inhibitor, dovitinib, and explore the mechanism of action of the drug-resistant mutations. We cultured BaF3 cells overexpressing FGFR2 in high concentrations of dovitinib and identified 14 dovitinib-resistant mutations, including the N550K mutation observed in 25% of FGFR2(mutant) endometrial cancers (ECs). Structural and biochemical in vitro kinase analyses, together with BaF3 proliferation assays, showed that the resistance mutations elevate the intrinsic kinase activity of FGFR2. BaF3 lines were used to assess the ability of each mutation to confer cross-resistance to PD173074 and ponatinib. Unlike PD173074, ponatinib effectively inhibited all the dovitinib-resistant FGFR2 mutants except the V565I gatekeeper mutation, suggesting ponatinib but not dovitinib targets the active conformation of FGFR2 kinase. EC cell lines expressing wild-type FGFR2 were relatively resistant to all inhibitors, whereas EC cell lines expressing mutated FGFR2 showed differential sensitivity. Within the FGFR2(mutant) cell lines, three of seven showed marked resistance to PD173074 and relative resistance to dovitinib and ponatinib. This suggests that alternative mechanisms distinct from kinase domain mutations are responsible for intrinsic resistance in these three EC lines. Finally, overexpression of FGFR2(N550K) in JHUEM-2 cells (FGFR2(C383R)) conferred resistance (about five-fold) to PD173074, providing independent data that FGFR2(N550K) can be associated with drug resistance. Biochemical in vitro kinase analyses also show that ponatinib is more effective than dovitinib at inhibiting FGFR2(N550K). We propose that tumors harboring mutationally activated FGFRs should be treated with FGFR inhibitors that specifically bind the active kinase. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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FGFR2 | E566G | missense | gain of function | FGFR2 E566G (corresponds to E565G in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). E566G results in increased Fgfr2 kinase activity and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597). | Y |
FGFR2 | I548V | missense | gain of function | FGFR2 I548V lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). I548V confers a gain of function on the Fgfr2 protein, as demonstrated by increased Fgfr2 kinase activity and enhanced cell proliferation in the presence of ligand in cell culture (PMID: 23908597). | |
FGFR2 | K641N | missense | gain of function | FGFR2 K641N lies within the protein kinase domain of the Fgfr2b protein (UniProt.org). K641N (reported as K642N) results in increased Fgfr2 kinase activity and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597). | |
FGFR2 | L618M | missense | gain of function | FGFR2 L618M (corresponds to L617M in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). L618M results in increased Fgfr2 kinase activity, enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597), and elevated kinase activity compared to wild-type Fgfr2 protein in substrate phosphorylation assays (PMID: 28166054). | |
FGFR2 | M536I | missense | gain of function | FGFR2 M536I (corresponds to M535I in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). M536I results in increased Fgfr2 kinase activity and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597). | |
FGFR2 | M538I | missense | gain of function | FGFR2 M538I (corresponds to M537I in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). M538I confers a gain of function to the Fgfr2 protein as demonstrated by increased Fgfr2 kinase activity (PMID: 32723837, PMID: 23908597) and enhanced cell proliferation in the presence of ligand in cell culture (PMID: 23908597), and has been associated with decreased sensitivity to some FGFR inhibitors (PMID: 23908597). | |
FGFR2 | N550H | missense | gain of function | FGFR2 N550H (corresponds to N549H in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N550H results in increased Fgfr2 kinase activity, as well as increased Fgfr2 phosphorylation and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597). | Y |
FGFR2 | N550K | missense | gain of function | FGFR2 N550K (corresponds to N549K in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N550K results in increased Fgfr2 kinase activity (PMID: 32723837, PMID: 23908597) and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597). | |
FGFR2 | N550S | missense | gain of function | FGFR2 N550S lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N550S results in increased Fgfr2 kinase activity and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597). | |
FGFR2 | N550T | missense | gain of function | FGFR2 N550T (corresponds to N549T in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N550T results in increased Fgfr2 kinase activity and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597). | |
FGFR2 | V565I | missense | gain of function | FGFR2 V565I (corresponds to V564I in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V565I results in increased Fgfr2 kinase activity and enhanced cell proliferation in the presence of ligand in culture (PMID: 23908597). | Y |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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FGFR2 E566G | Advanced Solid Tumor | sensitive | Ponatinib | Preclinical | Actionable | In a preclinical study, Iclusig (ponatinib) inhibited Fgfr2 phosphorylation and proliferation in transformed cells expressing FGFR2 E566G (PMID: 23908597). | 23908597 |
FGFR2 E566G | Advanced Solid Tumor | resistant | PD173074 | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 E566G were resistant to treatment with PD173074 (PMID: 23908597). | 23908597 |
FGFR2 K660E | Advanced Solid Tumor | decreased response | PD173074 | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 K660E demonstrated a decreased response when treated with PD173074 (PMID: 23908597). | 23908597 |
FGFR2 N550H | Advanced Solid Tumor | decreased response | Dovitinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 N550H demonstrated a decreased response to treatment with Dovitinib (TKI258) (PMID: 23908597). | 23908597 |
FGFR2 K660E | Advanced Solid Tumor | sensitive | Ponatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Iclusig (ponatinib) inhibited growth of transformed cells expressing FGFR2 K660E in culture (PMID: 23908597). | 23908597 |
FGFR2 N550K | Advanced Solid Tumor | sensitive | Ponatinib | Preclinical | Actionable | In a preclinical study, Iclusig (ponatinib) inhibited Fgfr2 phosphorylation and proliferation in transformed cells expressing FGFR2 N550K (PMID: 23908597). | 23908597 |
FGFR2 M536I | Advanced Solid Tumor | decreased response | Dovitinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 M536I demonstrated a decreased response to treatment with Dovitinib (TKI258) (PMID: 23908597). | 23908597 |
FGFR2 N550S | Advanced Solid Tumor | decreased response | PD173074 | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 N550S demonstrated a decreased response to treatment with PD173074 (PMID: 23908597). | 23908597 |
FGFR2 I548V | Advanced Solid Tumor | decreased response | Dovitinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 I548V demonstrated a decreased response to treatment with Dovitinib (TKI258) (PMID: 23908597). | 23908597 |
FGFR2 N550H | Advanced Solid Tumor | sensitive | Ponatinib | Preclinical | Actionable | In a preclinical study, Iclusig (ponatinib) inhibited Fgfr2 phosphorylation and proliferation in transformed cells expressing FGFR2 N550H (PMID: 23908597). | 23908597 |
FGFR2 M538I | Advanced Solid Tumor | decreased response | Ponatinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 M538I demonstrated a decreased response to treatment with Iclusig (ponatinib) (PMID: 23908597). | 23908597 |
FGFR2 N550K | Advanced Solid Tumor | resistant | Dovitinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 N550K were resistant to treatment with Dovitinib (TKI258) (PMID: 23908597). | 23908597 |
FGFR2 V565I | Advanced Solid Tumor | resistant | Ponatinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 V565I were resistant to treatment with Iclusig (ponatinib) (PMID: 23908597). | 23908597 |
FGFR2 N550K | Advanced Solid Tumor | resistant | PD173074 | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 N550K were resistant to PD173074 (PMID: 23908597). | 23908597 |
FGFR2 N550S | Advanced Solid Tumor | sensitive | Ponatinib | Preclinical | Actionable | In a preclinical study, Iclusig (ponatinib) inhibited Fgfr2 phosphorylation and proliferation in transformed cells expressing FGFR2 N550S (PMID: 23908597). | 23908597 |
FGFR2 K660E | Advanced Solid Tumor | resistant | Dovitinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 K660E were resistant to treatment with Dovitinib (TKI258) (PMID: 23908597). | 23908597 |
FGFR2 L618M | Advanced Solid Tumor | decreased response | Dovitinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 L618M demonstrated a decreased response to treatment with Dovitinib (TKI258) (PMID: 23908597). | 23908597 |
FGFR2 C383R FGFR2 N550K | endometrial cancer | resistant | PD173074 | Preclinical | Actionable | In a preclinical study, an endometrial cancer cell line harboring FGFR2 C383R and expressing FGFR2 N550K demonstrated resistance when treated with PD173074 (PMID: 23908597). | 23908597 |
FGFR2 E566G | Advanced Solid Tumor | resistant | Dovitinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 E566G were resistant to treatment with Dovitinib (TKI258) (PMID: 23908597). | 23908597 |
FGFR2 M538I | Advanced Solid Tumor | decreased response | Dovitinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 M538I demonstrated a decreased response to treatment with Dovitinib (TKI258) (PMID: 23908597). | 23908597 |
FGFR2 L618M | Advanced Solid Tumor | sensitive | Ponatinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 L618M were sensitive to treatment with Iclusig (ponatinib) (PMID: 23908597). | 23908597 |
FGFR2 N550S | Advanced Solid Tumor | decreased response | Dovitinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 N550S demonstrated a decreased response to treatment with Dovitinib (TKI258) (PMID: 23908597). | 23908597 |
FGFR2 N550H | Advanced Solid Tumor | resistant | PD173074 | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 N550H were resistant to treatment with PD173074 (PMID: 23908597). | 23908597 |
FGFR2 M536I | Advanced Solid Tumor | sensitive | Ponatinib | Preclinical | Actionable | In a preclinical study, Iclusig (ponatinib) inhibited Fgfr2 phosphorylation and proliferation in transformed cells expressing FGFR2 M536I (PMID: 23908597). | 23908597 |
FGFR2 V565I | Advanced Solid Tumor | resistant | PD173074 | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 V565I were resistant to treatment with PD173074 (PMID: 23908597). | 23908597 |
FGFR2 V565I | Advanced Solid Tumor | resistant | Dovitinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 V565I were resistant to treatment with Dovitinib (TKI258) (PMID: 23908597). | 23908597 |
FGFR2 M536I | Advanced Solid Tumor | decreased response | PD173074 | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 M536I demonstrated a decreased response to treatment with PD173074 (PMID: 23908597). | 23908597 |
FGFR2 L618M | Advanced Solid Tumor | decreased response | PD173074 | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 L618M demonstrated a decreased response to treatment with PD173074 (PMID: 23908597). | 23908597 |
FGFR2 I548V | Advanced Solid Tumor | sensitive | Ponatinib | Preclinical | Actionable | In a preclinical study, Iclusig (ponatinib) inhibited Fgfr2 phosphorylation and proliferation in transformed cells expressing FGFR2 I548V (PMID: 23908597). | 23908597 |
FGFR2 I548V | Advanced Solid Tumor | decreased response | PD173074 | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 I548V demonstrated a decreased response to treatment with PD173074 (PMID: 23908597). | 23908597 |
FGFR2 M538I | Advanced Solid Tumor | decreased response | PD173074 | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 M538I demonstrated a decreased response to treatment with PD173074 (PMID: 23908597). | 23908597 |
FGFR2 S252W | Advanced Solid Tumor | conflicting | Dovitinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing FGFR2 S252W were sensitive to Dovitinib (TKI258) (PMID: 23908597). | 23908597 |